Furane-dicarboxylic-acid-amides and their manufacture



Patented Apr. 20, 1943 UNITED STATES PATENT OFFICEFUBIANE-DICARBOXYLIC-ACID-AMIDES AND THEIR MANUFACTURE No Drawing.Application December 20, 1940, Se-

rial No. 371,050. In Switzerland December 2,

7 Claims.

It has surprisingly been found that the furanedicarboxylic-acid-amidesor furane-dicarboxylicacid-ester-amides hitherto not known possessremarkable pharmocological properties which render them valuable fortherapeutical uses. The said new compounds can be obtained by causingiurane-dicarboxylic-acids or derivatives thereof, such as for exampletheir metal salts, halides, esters or anhydrides, to react withsecondary amines or their salts or with 'carbamic-acidhalides in thepresence or absence of solvents, condensation agents and acid bindingagents.

As condensation agents there may preferably be used phosphorus halides,phosphorus pentoxide, thionyl chloride as well as phosgehe and so on.

The new compounds distinguish themselves especially by their excellentanaleptical effects. The furane-dicarboxylic-acid-amides orfuranedicarboxylic acid ester amides hitherto not known are in part verywell soluble in water, in part soluble in alcohol, ether, chloroform,glycolether or propylene-glycol.

The invention is illustrated, but not limited, by the followingexamples, in which the parts are by weight, where nothing other is said.

Example 1 44 parts by weight of2-methylfurane-5-aceticacid-3-carboxylic-acid-dichloride (B. P. at 1.4mm. 130 C.) made from the corresponding acid with thionyl-chloride, aredissolved in 500 parts by volume of absolute ether and a solution of 36parts by weight of diethyl-amine in 400 parts by volume of absoluteether is, under stirring and cooling (at 10 C.), added drop by dropthereto. When all of the amine is dropped in, the temperature is allowedto raise up to room-temperature and the mixture is then warmed for still2 hours up to 25 C. Thereupon the diethylamine-chlorhydrate separatedout is sucked ch in order to then treat the ethereal solution with asaturated potassium-carbonate solution. Thereupon there is dried oversodium sulfate. The ether having been expelled, the Z-methylfurane-5-acetic-3-carboxylic-acid-bis-diethyl-amide dis tils at 0.5 mm. and 185C. as a weakly yellow colored oil. It is mixable in any proportion withwater.

In the same manner the following compounds may be prepared:

Instead of 2 molecules of the organic base there may also be used onlyone molecule thereof and the acid becoming free be bound by a carbonatesuch as anhydrous sodium carbonate.

Example 2 22 parts of2-methylfurane-5-acetic-3-carboXylic-acid-dichloride or the equivalentquantity of the corresponding dibromide are heated with 20 parts ofdiethylamine-chlorhydrate during 2 hours up to about 160 C. The obtainedmelt is dissolved in water, then a caustic alkali is added thereto andthe whole is shaken out with ether. The ethereal solution is dried,concentrated by evaporation and purified by distillation. The samebis-diethylamide as that of Example 1 is obtained.

Instead of the hydrochloride another salt can also be used.

Example 3 15 parts of the disodium salt of the-methylfurane-Z-acetic-3-carboxylic acid (or of another salt such as ofthe potassium salt) are heated up to about C. with 40 parts ofdiethylcarbamicacid-chloride. Under development of carbonic acid astormy reaction to the bis-diethylamide of the 4-methylfurane 2 acetic 3carboxylic acid takes place. The same is dissolved in ether and washedwith water; after drying and evaporating the solvent, thebis-diethylamide is obtained in form of a nearly colorless liquidboiling at 158-160 C. (at 0.65 mm.).

Instead of the diethylcarbamic-acid-chloride the corresponding quantityof the dimethyl compound may also be used.

In the same manner as the 4-rnethylfurane-2- acetic-3-carboxylic acidthe furane-2-acetic-3- carboxylic acid, the 4-cthylfurane-Z-acetic-3-carboxylic acid or the 4:5-dimethylfurane-2- acetic-3-carboxylic acidcan also be converted into the bis-diethylamide. The reaction takesplace in the same manner if, instead of these dium salt, other saltssuch as for instance calcium salts, are used. a

Example 4 20 parts by weight ofztnyirtranas-aeetic-acid-ethylester-3-carboxylic acid chloride, 13. P.at 12 mm. Mil-147 0., prepared from 2-methylfuraneacetic-acid-ethylester 3 carb oxylic acid and thionylchloride, are dissolved in ether, then mixed with the calculatedquantity of diethylamine and the whole is kept for 2 hours at 25 C;After filtration of separated diethylamine-chlorhydrate the etherealsolution is washed with water, then dried and afterwards the ether isexpelled. The residue, the Z-methylfurane-5-acetic-acid-ethylester 3carboxylicacid-diethylamide, forms a bright oil with a boil-- ing pointof loll-162 C. at 1 mm. pressure.

Eivample 5 18 parts of 2:5-dimethylfurane-3: l-dicarboX-ylic-acid-chloride, B. P. at 14 mm. 135-l37 0., made from 25-dimethylfurane-3 l-dicarboxylic acid and thionyl chloride, aredissolved in absolute ether and mixed with 24 parts of diethylamine.Diethylamine-chlorhydrate is at once separated out. After a standing fortwo hours the said chlorhydrate is sucked off, the ether is washed witha saturated potassium carbonate solution, then dried with potassiumhydroxide and evaporated. The residue, the2:5-dimethylfurane-3:4-dicarboxylic acid bis cliethylamide, boils at 15i-156 C., and 0.4 pressure. crystallised from petroleum ether it formsgreat transparent crystals of a melting point of 62 C. It is clearlysoluble in water.

Instead of the chloride the anhydride can also be used.

Example 6 8 parts of 2:4-furanedicarboxylic-acid-chloride,made from2:4-furanedicarboxylic-acid and thionylchloride, are dissolved inabsolute benzene and mixed with the calculated quantity of diethylamine.The mixture is heated during several hours up to 40 C. and after somestanding the chlorhydrate separated out is filtered off. The benzenesolution is treated with a concentrated caustic alkali and then driedwith solid potassium hydroxide. After the evaporation of the benzene the2z l-furane-dicarboxylic-acidbis-diethylamide remains as a water-solublesubstance.

In the same manner the 2:5-furane-dicarboxylic-acid-bis-diethylamide maybe produced.

Example 7 7 parts of2-methylfurane-5acetic-dwarboxylic-acid-diphenylester, made by heating2- methylfurane-5acetic-3 carboxylic acid di-' chloride and phenol in abenzene solution, are heated in the tube for several hours up to 160 C.with 50 parts of diethylamine. From the reaction mixture there results,as in Example 1, methronic-acid-bis-diethylamide.

Example 8 20 parts of 2-n1ethylfurane-5-acetic-3carboxylic-acid aretransformed into the diethylamine salt and heated up to about C. underaddition of 25 parts of phosphorus oxychloride. The transformation beingfinished, the resulting product is worked up as described in Example 1-.Thus methronic-acid-bis-diethyl-amide is obtained.

Instead of phosphorus oxychloride one may also use phosphorus pentoxide.

What we claim is:

1. The amides of furane-dicarboxylic acids of the following generalformula /a CON wherein X means a member of the group consisting of H andalkyl, Y means a member of the group consisting of CH2 and the directlinkage,-

n being one to two, and a, b, c, at mean monovalent radicals selectedfrom the group consisting of alkyl, cycloalkyl and aryl radicals of thebenzene series, and the couples a b and c d mean divalent aliphaticradicals, prepared for use as therapeutics.

2. The amides of furane-dicarboxylic acids of the following generalformula wherein X means a member of the group consisting of H and alkyl,it being. one to two, prepared for use as therapeutics.

4. The diethylam'ids of rurane-uicarboxylic' acids of the followinggeneral formula V wherein X means a member of the group consisting ofHand alkyl, and n. being one to two, the said diethylamides pre ared foruse as a them-- peutic.

5. The 2-methylfurane-5-acetic-3-carboxylic- 7. Thefurane-2-acetic-3-ca.rboxylic-acid-bisacid-bis-diethylamide of thefollowing formula diethylamide of the following formula (2-0-00 N(C H)911:0

prepared for use as a therapeutic.

6. The 2.5-dimethylfurane 3.4 dicarboxylicacid-bisdiethylamide of thefollowing formula 10 prepared for use as a. therapeutic.

HENRY MARTIN.

0H: WALTER BAUMANNQ ';=G 1 HANS GYSIN.

l 2 l): CH:

prepared for use as a therapeutic.

